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Combination of radioimmunotherapy with growth inhibition for antibody-based therapy of L1 expressing metastases

English title Combination of radioimmunotherapy with growth inhibition for antibody-based therapy of L1 expressing metastases
Applicant Novak-Hofer Ilse
Number 116185
Funding scheme Project funding (Div. I-III)
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Experimental Cancer Research
Start/End 01.05.2007 - 30.09.2008
Approved amount 83'064.00
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Keywords (5)

anti-L1 antibody chCE7; radioimmunotherapy; 67-Cu labeling; 67-Cu PET imaging; ovarian cancer metastases

Lay Summary (English)

Lead
Lay summary
We have used the high affinity monoclonal antibody chCE7 which is directed against the L1 cell adhesion molecule originally to develop radioimmunotherapy (RIT) for metastatic neuroblastoma. In the past years it emerged that the L1 protein is also highly expressed in subsets of renal carcinomas, melanomas and in ovarian- and endometrial carcinomas. The growth promoting and anti-apoptotic properties, which L1 expression confers to tumor cells, give a rationale for anti-L1 antibody based therapies. Recently antibody therapy directed against the L1 protein has come forth as a new option for targeting ovarian cancer metastases as we showed that anti-L1 antibodies L1-11A and chCE7 inhibit proliferation of SKOV3ip human ovarian cancer cells in vitro and growth of SKOV3ip metastases in vivo in nude mice. Our goal is to develop strategies to increase the effectiveness of RIT using anti-L1 antibodies by introducing novel beta-particle emitting radionuclides such as 67Cu or 177Lu and by searching for effective combinations with other treatment modalities. For RIT we will use the medium energy beta particle emitting nuclides 67Cu and 177Lu, 64Cu will be used for PET imaging. The nuclides will be linked to an aglycosylated mutant of mAb chCE7 (chCE7agl) which is characterized by more rapid clearance from the blood than the parent antibody. We found that this antibody format circumvents the problems encountered with rapidly clearing radiometal-labeled antibody fragments, which consist in low tumor uptake and the accumulation of radioactivity in the kidneys. Therapeutic effects of 67Cu- and 177Lu-labeled chCE7agl will be assessed in the orthotopic SKOV3ip metastases model in nude mice. PET imaging with 64Cu-labeled antibodies will be used to follow therapies. Marker proteins for proliferation and microvessel density will be analysed in tumors from treatment groups. We will investigate if recurrence after RIT can be delayed by inhibiting metastatic repopulation in the peritoneal cavity with unlabeled growth inhibiting anti-L1 antibodies. In view of the growth signaling properties of the L1 protein, multitargeted tyrosine kinase inhibitors and tyrosine kinase inhibitors specific for EGF and VEGF receptors will be evaluated in combination with RIT and/or growth inhibition. Results on cooperative effects between L1-targeted RIT, therapy with unlabeled anti-L1 antibodies and growth inhibiting tyrosine kinase inhibitors may lead to novel approaches for treatment of metastatic ovarian cancer.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
120158 Novel enzymatic methods for the site-specific modification of therapeutic proteins 01.05.2008 Project funding (Div. I-III)

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